The overriding goals of this competing renewal application are to understand the interactions between host immunity and viral replication, evolution and fitness, during and beyond acute HIV-1 infection. Our work is targeted to the goals of enhancing control and prevention of infection. The first 5 years of support for this work have been very productive, yielding important insight into early infection host-pathogen dynamics, the impact on viral fitness that occurs as a result of immune escape, the dynamics and cellular site of virus in HIV-1 exposed individuals that remain seronegative, therapeutic interventions, and the use of this data in the formulation of state-of-the-art vaccine immunogen designs. Our program is unique in that we focus on in-depth, multifaceted analysis of subjects that were enrolled while in acute HIV-1 B infection and then followed longitudinally for many years. Our additional foci on donor-recipient partner pairs and viral fitness represent state of the art leadership in these areas. In this renewal, we have added a new Project and the new dimension of evaluation of initially HIV-discordant couples and subsequent heterosexual transmission involving HIV-1 subtypes A, C and D. Our studies are critically important to the continuation of our growing understanding of primary HIV infection and to the design of protective HIV vaccines. State-of-the-art immunological, genetic and virologic technologies will be brought to bear to further dissect the biological mechanisms underlying host control, in three highly interactive research projects. Our Program is composed of three Projects that combine the areas of viral evolution and adaptation to host immunogenetics and cellular immune responses. We also have four Cores, covering the essential elements of Administration, Clinical, Virological and Repository, and Biostatistics functions.